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Non-nutritive Sweeteners Induce Hypothalamic ER Stress Causing Abnormal Axon Outgrowth.

ABSTRACT: With the prevalence of obesity, non-nutritive sweeteners (NNS) have been widely used as sugar substitutes as they deliver a sweet taste without excessive caloric load. However, it is increasingly recognized that NNS are not inert compounds and may cause long-term metabolic perturbations. Endoplasmic reticulum (ER) stress has emerged as a critical link in the development of obesity and type 2 diabetes. In this study, we investigated the effects of NNS found in common diet beverages (i.e., sucralose, aspartame, acesulfame potassium) and a natural sweetener (i.e., rebaudioside A) on ER stress in the hypothalamic cell line mHypoE-N43/5 in vivo and on axonal outgrowth ex vivo. Sucralose, aspartame, and acesulfame potassium caused elevated ER stress gene expression in mHypoE-N43/5 cells, with sucralose and acesulfame potassium having the most potent effect. Moreover, acesulfame potassium treatment reduced axon outgrowth from arcuate nucleus explants and this effect was attenuated with the ER stress-relieving drug tauroursodeoxycholic acid. Furthermore, sucralose induced cytotoxicity and acesulfame potassium increases caspase3/7 activity at high concentrations in mHypoE-N43/5 cells. In contrast, rebaudioside A only had moderate effects on hypothalamic ER stress and no adverse effects on axon outgrowth, cytotoxicity, or caspase3/7 activity. Together, our data reveal that commonly consumed NNS cause cellular stress in hypothalamic cells disrupting axon outgrowth and that these biological alterations are not seen with rebaudioside A. These data provide biological plausibility for some NNS to adversely impact metabolic health and identifies rebaudioside A as a sweetener with lower detrimental biological impact on hypothalamic cells.

SUBMITTER: Park S

PROVIDER: S-EPMC6928131 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Non-nutritive Sweeteners Induce Hypothalamic ER Stress Causing Abnormal Axon Outgrowth.

Park Soyoung S Sethi Sunjay S Bouret Sebastien G SG

Frontiers in endocrinology 20191217

With the prevalence of obesity, non-nutritive sweeteners (NNS) have been widely used as sugar substitutes as they deliver a sweet taste without excessive caloric load. However, it is increasingly recognized that NNS are not inert compounds and may cause long-term metabolic perturbations. Endoplasmic reticulum (ER) stress has emerged as a critical link in the development of obesity and type 2 diabetes. In this study, we investigated the effects of NNS found in common diet beverages (i.e., sucralo ...[more]

PMID: 31920985

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Project description:Recent studies suggest that preferences are conditioned by nutritive (sucrose) but not by non-nutritive (sucralose) sweeteners in mice. Here we compared the effectiveness of nutritive and non-nutritive sweeteners to condition flavor preferences in three mouse strains. Isopreferred sucrose and sucralose solutions both conditioned flavor preferences in C57BL/6J (B6) mice but sucrose was more effective, consistent with its post-oral appetition action. Subsequent experiments compared flavor conditioning by fructose, which has no post-oral appetition effect in B6 mice, and a sucralose+saccharin mixture (SS) which is highly preferred to fructose in 24-h choice tests. Both sweeteners conditioned flavor preferences but fructose induced stronger preferences than SS. Training B6 mice to drink a flavored SS solution paired with intragastric fructose infusions did not enhance the SS-conditioned preference. Thus, the post-oral nutritive actions of fructose do not explain the sugar's stronger preference conditioning effect. Training B6 mice to drink a flavored fructose solution containing SS did not reduce the sugar-conditioned preference, indicating that SS does not have an off-taste that attenuates conditioning. Although B6 mice strongly preferred flavored SS to flavored fructose in a direct choice test, they preferred the fructose-paired flavor to the SS-paired flavor when these were presented in water. Fructose conditioned a stronger flavor preference than an isopreferred saccharin solution, indicating that sucralose is not responsible for the limited SS conditioning actions. SS is highly preferred by FVB/NJ and CAST/EiJ inbred mice, yet conditioned only weak flavor preferences. It is unclear why highly or equally preferred non-nutritive sweeteners condition weaker preferences than fructose, when all stimulate the same T1r2/T1r3 sweet receptor. Recent findings support the existence of non-T1r2/T1r3 glucose taste sensors; however, there is no evidence for receptors that respond to fructose but not to non-nutritive sweeteners.

Project description:BackgroundThe mechanisms by which chronic stress increases the risk of non-communicable diseases remain poorly understood. On one hand, chronic stress may increase systemic vascular resistance (SVR) and blood pressure, which may lead to blood vessels injury and altered myocardial perfusion. On the other hand, chronic stress may promote the overconsumption of sugar-containing foods and favor obesity. There is indeed evidence that sweet foods are preferentially consumed to alleviate stress responses. The effects of nutritive and non-nutritive sweeteners (NNS) on hemodynamic stress responses remain however largely unknown.Objective/designThis study aimed at comparing the effects of sucrose-containing and NNS-containing drinks, as compared to unsweetened water, on hemodynamic responses to acute stress in twelve healthy female subjects. Acute stress responses were elicited by a 30-min mental stress (5-min Stroop's test alternated with 5-min mental arithmetic) and a 3-min cold pressure test (CPT), each preceded by a resting baseline period. Hemodynamic stress responses were investigated by the repeated measurement of mean arterial pressure and the continuous monitoring of cardiac output by thoracic electrical bioimpedance measurement. SVR was selected as a primary outcome because it is a sensitive measure of hemodynamic responses to acute stress procedures.ResultsWith all three drinks, SVR were not changed with mental stress (P = 0.437), but were increased with CPT (P = 0.045). Both mental stress and CPT increased mean arterial pressure and heart rate (all P < 0.001). Cardiac output increased with mental stress (P < 0.001) and remained unchanged with CPT (P = 0.252). No significant differences in hemodynamic responses were observed between water, sucrose and NNS (stress × condition, all P > 0.05).ConclusionsThese results demonstrate that sucrose and NNS do not alter hemodynamic responses to two different standardized acute stress protocols.

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Non-nutritive Sweeteners Induce Hypothalamic ER Stress Causing Abnormal Axon Outgrowth.

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Non-nutritive Sweeteners Induce Hypothalamic ER Stress Causing Abnormal Axon Outgrowth.

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